Prognostic Impact of Histologic Grade for Papillary Thyroid Carcinoma.

BACKGROUND: While numerous factors affect prognosis in papillary thyroid carcinoma (PTC), the comparative impact of histologic grade has not been well described. Moreover, indications for external beam radiation therapy (EBRT) remain imprecise. We evaluate clinicopathologic characteristics and outcomes for PTC stratified by grade. METHODS: We profiled histologic grade for PTC (well differentiated, moderately differentiated, poorly differentiated) via hospital (National Cancer Database) and population-based (Surveillance, Epidemiology, and End Results) registries. Cox regression was used to adjust for clinicopathologic covariates. Statistical interactions between subtypes and the effect of EBRT on survival were assessed. RESULTS: Collectively, worsening clinicopathologic factors (age, tumor size, extrathyroidal extension, nodal spread, M1 disease) and outcomes (disease-free survival, overall survival) correlated with less differentiated state, across all histologic grades (p < 0.001). Multivariable analysis showed escalating hazard with loss of differentiation relative to well-differentiated PTC (moderately differentiated hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.41, p = 0.02; poorly differentiated HR 2.62, 95% CI 2.23-3.08, p < 0.001). Correspondingly, greater survival benefit was associated with EBRT for poorly differentiated cases (HR 0.36, 95% CI 0.18-0.72, p = 0.004). This finding was upheld after landmark analysis to address potential immortal time bias (HR 0.37, 95% CI 0.17-0.80, p = 0.01). CONCLUSIONS: Worsening histologic grade in PTC is independently associated with parallel escalation in mortality risk, on a scale approximating or surpassing established thyroid cancer risk factors. On preliminary analysis, EBRT was associated with improved survival in the most aggressive or least differentiated subvariants. Further investigation is warranted to examine the efficacy of EBRT for select poorly differentiated thyroid carcinomas.

IS MEASUREMENT OF CIRCULATING TUMOR DNA OF DIAGNOSTIC USE IN PATIENTS WITH THYROID NODULES?

OBJECTIVE: Circulating tumor DNA (ctDNA), a subset of cell-free DNA (cfDNA), is a potential biomarker for thyroid cancer. We determined the performance of a ctDNA panel for detecting thyroid malignancy in patients with thyroid nodules. METHODS: Sixty-six patients with thyroid nodules without a prior history of cancer enrolled in a prospective, 1-year study in which blood was drawn for ctDNA analysis prior to undergoing fine-needle aspiration biopsy (FNAB) of thyroid nodules. The ctDNA panel consisted of 96-mutations in 9 cancer driver genes. The primary outcome measures were the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of our ctDNA panel for the diagnosis of thyroid malignancy as determined by pathologic and/or molecular tissue examination. RESULTS: Results from 10 subjects could not be determined due to inadequate volume or technical issues. The final classifications of the thyroid nodules were 13 malignant and 43 benign lesions. A KRAS G12V mutation was detected in the plasma of 1 patient with stage IVA papillary carcinoma whose tissue contained the same mutation. Two of the 43 patients with benign lesions also had ctDNA detected, giving a sensitivity of 7.7%, specificity of 95.35%, PPV of 33.33%, and NPV of 77.35%. There were no significant differences between benign or malignant lesions in cfDNA levels. CONCLUSION: Neither cfDNA measurements nor our panel of ctDNA mutations are sensitive or specific enough to provide valuable information over FNAB. An expanded panel and the inclusion of proteomics may improve sensitivity and specificity for thyroid cancer detection. ABBREVIATIONS: cfDNA = cell-free DNA; ctDNA = circulating tumor DNA; FNAB = fine-needle aspiration biopsy; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

LYMPHOCYTIC THYROIDITIS IS ASSOCIATED WITH INCREASED NUMBER OF BENIGN CERVICAL NODES AND FEWER CENTRAL NECK COMPARTMENT METASTATIC LYMPH NODES IN PATIENTS WITH DIFFERENTIATED THYROID CANCER.

OBJECTIVE: Whether or not autoimmune thyroid disease influences the progression of differentiated thyroid cancer (DTC) remains controversial. Findings of previous studies are influenced by lead time bias and/or procedure bias selection. These biases can be reduced by studying a single-institution patient population that underwent a similar extent of surgical resection. METHODS: From a cohort of 660 patients with DTC who underwent thyroidectomy, we retrospectively studied 357 patients who underwent total thyroidectomy and central compartment node dissection (CCND) for DTC between 2003 and 2013. RESULTS: Forty-one percent (140/345) of study patients had lymphocytic thyroiditis (LT), and 30% (91/301) had serum positive for thyroglobulin antibody (TgAb). LT was reported in 78% of the TgAb-positive cases. Sixty percent (213/357) of cases had metastatic thyroid carcinoma in 1 or more neck lymph nodes (55% [198/357] central compartment, and 22% [77/356] lateral compartment). Patients with LT had fewer metastatic cervical lymph nodes than those with no LT (2.7 ± 4.7 vs 3.5 ± 4.8, respectively, P = .0285). Patients with positive TgAb and thyroiditis had a larger number of benign cervical lymph nodes removed than those with negative TgAb or no LT. No significant difference was observed in age, tumor size, multifocality, extrathyroidal extension, vascular invasion, or frequency of cervical lymph node metastasis between TgAb-negative and -positive cases or between cases with and without LT. CONCLUSION: Lymphocytic thyroiditis is associated with fewer central neck compartment metastatic lymph nodes and a larger number of excised reactive benign cervical lymph nodes. Whether this association indicates a protective role of thyroid autoimmunity in lymph node spreading remains unclear. ABBREVIATIONS: CCND = central compartment node dissection DTC = differentiated thyroid cancer HT = Hashimoto thyroiditis LT = lymphocytic thyroiditis TgAb = thyroglobulin antibody TPO = thyroid peroxidase.

Global clinical response in Cushing's syndrome patients treated with mifepristone.

OBJECTIVE: Mifepristone, a glucocorticoid receptor antagonist, improves clinical status in patients with Cushing's syndrome (CS). We examined the pattern, reliability and correlates of global clinical response (GCR) assessments during a 6-month clinical trial of mifepristone in CS. DESIGN: Post hoc analysis of secondary end-point data from a 24-week multicentre, open-label trial of mifepristone (300-1200 mg daily) in CS. Intraclass correlation coefficient (ICC) was used to examine rater concordance, and drivers of clinical improvement were determined by multivariate regression analysis. PATIENTS: Forty-six adult patients with refractory CS along with diabetes mellitus type 2 or impaired glucose tolerance, and/or a diagnosis of hypertension. MEASUREMENTS: Global clinical assessment made by three independent reviewers using a three-point ordinal scale (+1 = improvement; 0 = no change; -1 = worsening) based on eight broad clinical categories including glucose control, lipids, blood pressure, body composition, clinical appearance, strength, psychiatric/cognitive symptoms and quality of life at Weeks 6, 10, 16, and 24. RESULTS: Positive GCR increased progressively over time with 88% of patients having improved at Week 24 (P < 0·001). The full concordance among reviewers occurred in 76·6% of evaluations resulting in an ICC of 0·652 (P < 0·001). Changes in body weight (P < 0·0001), diastolic blood pressure (P < 0·0001), two-hour postoral glucose challenge glucose concentration (P = 0·0003), and Cushingoid appearance (P = 0·022) were strong correlates of GCR. CONCLUSIONS: Mifepristone treatment for CS results in progressive clinical improvement. Overall agreement among clinical reviewers was substantial and determinants of positive GCR included change in weight, blood pressure, glucose levels and appearance.

Evolving approaches in managing radioactive iodine-refractory differentiated thyroid cancer.

OBJECTIVE: To discuss the approach to care of patients with advanced differentiated thyroid cancer (DTC), in particular those with radioactive iodine (RAI)-refractory disease, and the transition to systemic treatment. METHODS: A PubMed search was conducted using the search terms "radioactive iodine-refractory, differentiated thyroid cancer and treatment" restricted to a 2000-2012 timeframe, English language, and humans. Relevant articles were identified from the bibliographies of selected references. Four patient cases are presented to illustrate the clinical course of RAI-refractory DTC. RESULTS: The current standard of care for early stage DTC could include surgery, RAI in some cases, and thyroid hormone suppression. For advanced RAI-refractory DTC, clinical practice guidelines established by the National Comprehensive Cancer Network and the American Thyroid Association recommend, as one option, the use of systemic therapy, including kinase inhibitors. Numerous trials are underway to evaluate the clinical benefit of these targeted therapies. CONCLUSION: Preliminary results are encouraging with respect to the clinical benefit of targeted systemic therapies. However, at present there is no consensus on the criteria that define RAI-refractory disease and the optimal timing for transition to systemic therapy. There remains a need to establish common criteria to enhance patient care and enable better comparison across clinical studies.

Fifteen-Year History of Virilization in a 17th-Century Woman.

The Spanish artist, Jusepe de Ribera, painted a portrait of a virilized woman in 1631. He provided a brief clinical history on stone tablets, which indicates that the woman most likely harbored a benign, androgen-secreting ovarian tumor for 15 years.

Early recognition of risk factors for adverse outcomes during hospitalization among Medicare patients: a prospective cohort study.

BACKGROUND: There is a persistently high incidence of adverse events during hospitalization among Medicare beneficiaries. Attributes of vulnerability are prevalent, readily apparent, and therefore potentially useful for recognizing those at greatest risk for hospital adverse events who may benefit most from preventive measures. We sought to identify patient characteristics associated with adverse events that are present early in a hospital stay. METHODS: An interprofessional panel selected characteristics thought to confer risk of hospital adverse events and measurable within the setting of acute illness. A convenience sample of 214 Medicare beneficiaries admitted to a large, academic medical center were included in a quality improvement project to develop risk assessment protocols. The data were subsequently analyzed as a prospective cohort study to test the association of risk factors, assessed within 24 hours of hospital admission, with falls, hospital-acquired pressure ulcers (HAPU) and infections (HAI), adverse drug reactions (ADE) and 30-day readmissions. RESULTS: Mean age = 75(±13.4) years. Risk factors with highest prevalence included >4 active comorbidities (73.8%), polypharmacy (51.7%), and anemia (48.1%). One or more adverse hospital outcomes occurred in 46 patients (21.5%); 56 patients (26.2%) were readmitted within 30 days. Cluster analysis described three adverse outcomes: 30-day readmission, and two groups of in-hospital outcomes. Distinct regression models were identified: Weight loss (OR = 3.83; 95% CI = 1.46, 10.08) and potentially inappropriate medications (OR = 3.05; 95% CI = 1.19, 7.83) were associated with falls, HAPU, procedural complications, or transfer to intensive care; cognitive impairment (OR = 2.32; 95% CI = 1.24, 4.37), anemia (OR = 1.87; 95% CI = 1.00, 3.51) and weight loss (OR = 2.89; 95% CI = 1.38, 6.07) were associated with HAI, ADE, or length of stay >7 days; hyponatremia (OR = 3.49; 95% CI = 1.30, 9.35), prior hospitalization within 30 days (OR = 2.66; 95% CI = 1.31, 5.43) and functional impairment (OR = 2.05; 95% CI = 1.02, 4.13) were associated with 30-day readmission. CONCLUSIONS: Patient characteristics recognizable within 24 hours of admission can be used to identify increased risk for adverse events and 30-day readmission.

Are Prepubertal Gynaecomastia and Premature Thelarche Linked to Topical Lavender and Tea Tree Oil Use?

Various studies, conducted since 2007, have reported a total of eight boys with prepubertal gynaecomastia and four girls with premature thelarche following exposure to lavender and/or tree tea oil. All patients experienced regression of the breast tissue after they stopped using these oils. Both of these essential oils, and several of their constituents, have oestrogenic and antiandrogenic activity in vitro. However, limited dermal penetration of some of the components means that the in vitro findings cannot be extrapolated to the in vivo situation. There are unanswered questions as to how much lavender or tea tree oil was actually present in the skincare products used by the children and a lack of information about exposure to other agents. Furthermore, since both prepubertal gynaecomastia and premature thelarche often spontaneously regress, it cannot be concluded that the use of lavender and/or tree tea oil is the cause of the gynaecomastia and thelarche in these children.

Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women.

INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is a common problem in postmenopausal women, but in the absence of an approved medical treatment in the United States, off-label testosterone use is widespread. Large, randomized controlled studies have demonstrated that transdermal testosterone improves sexual function and activity in postmenopausal women and has favorable short-term safety. However, a longer-term safety profile of testosterone must be established before a testosterone product for women is approved. AIM: To review current knowledge of the efficacy and safety of transdermal testosterone based on presentations at a satellite symposium during the 2011 annual meeting of the International Society for the Study of Women's Sexual Health. METHODS: Pertinent information included in the presentations was augmented with relevant articles from the peer-reviewed literature. MAIN OUTCOME MEASURES: The rationale for testosterone therapy and results from phase III and other clinical studies with the testosterone patch in postmenopausal women with HSDD and findings from studies investigating the cardiovascular, breast, and endometrial effects of testosterone therapy. RESULTS: Randomized, double-blind, placebo-controlled studies have established the efficacy of the transdermal testosterone patch for relieving symptoms of HSDD in surgically and naturally menopausal women with and without concomitant estrogen or estrogen/progestin therapy. The main side effects reported in clinical trials were increased hair growth and acne. Available safety data for testosterone, although not conclusive, were reassuring with respect to cardiovascular, breast, and endometrial outcomes. Interim data from a long-term phase III safety trial of a testosterone gel demonstrate a continued low rate of cardiovascular events and breast cancer in postmenopausal women at increased cardiovascular risk. CONCLUSION: Transdermal testosterone appears to be an effective and safe therapy for postmenopausal women with HSDD.

Spurious Serum Hormone Immunoassay Results: Causes, Recognition, Management.

For over 50 years, immunoassays have been extensively used to quantitate hormones in blood, other fluids and tissues. Each assay has its own sensitivity, specificity and other analytical components. Despite the differences between commercial products, these assays provide important clinical information about hormone levels in patients. However, inaccurate results can occur because of technical issues, as well as patient-specific factors that can interfere with immunoassay hormone measurements. The latter include excessive normal blood or serum components, the presence of cross-reacting substances, extremely high levels of hormones leading to the high-dose hook effect, and interference from a variety of endogenous factors such as human antibodies that interact with the assay components or high levels of biotin in the serum from exogenous ingestion. This article briefly reviews the sources and recognition of endogenous interference, and describes methods to determine the correct serum hormone concentration.

Expanded Parameters in Active Surveillance for Low-risk Papillary Thyroid Carcinoma: A Nonrandomized Controlled Trial.

Importance: Unlike for prostate cancer, active surveillance for thyroid cancer has not achieved wide adoption. The parameters by which this approach is feasible are also not well defined, nor is the effect of patient anxiety. Objective: To determine if expanded size/growth parameters for patients with low-risk thyroid cancer are viable, as well as to assess for cohort differences in anxiety. Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a US academic medical center from 2014 to 2021, with mean [SD] 37.1 [23.3]-month follow-up. Of 257 patients with 20-mm or smaller Bethesda 5 to 6 thyroid nodules, 222 (86.3%) enrolled and selected treatment with either active surveillance or immediate surgery. Delayed surgery was recommended for size growth larger than 5 mm or more than 100% volume growth. Patients completed the 18-item Thyroid Cancer Modified Anxiety Scale over time. Interventions: Active surveillance. Main Outcomes and Measures: Cumulative incidence and rate of size/volume growth. Results: Of the 222 patients enrolled, the median (IQR) age for the study population was 46.8 (36.6-58) years, and 76.1% were female. Overall, 112 patients (50.5%) underwent treatment with active surveillance. Median tumor size was 11.0 mm (IQR, 9-15), and larger tumors (10.1-20.0 mm) comprised 67 cases (59.8%). One hundred one (90.1%) continued to receive treatment with active surveillance, 46 (41.0%) had their tumors shrink, and 0 developed regional/distant metastases. Size growth of more than 5 mm was observed in 3.6% of cases, with cumulative incidence of 1.2% at 2 years and 10.8% at 5 years. Volumetric growth of more than 100% was observed in 7.1% of cases, with cumulative incidence of 2.2% at 2 years and 13.7% at 5 years. Of 110 patients who elected to undergo immediate surgery, 21 (19.1%) had equivocal-risk features discovered on final pathology. Disease severity for all such patients remained classified as stage I. Disease-specific and overall survival rates in both cohorts were 100%. On multivariable analysis, immediate surgery patients exhibited significantly higher baseline anxiety levels compared with active surveillance patients (estimated difference in anxiety scores between groups at baseline, 0.39; 95% CI, 0.22-0.55; P < .001). This difference endured over time, even after intervention (estimated difference at 4-year follow-up, 0.50; 95% CI, 0.21-0.79; P = .001). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that a more permissive active surveillance strategy encompassing most diagnosed thyroid cancers appears viable. Equivocal-risk pathologic features exist in a subset of cases that can be safely treated, but suggest the need for more granular risk stratification. Surgery and surveillance cohorts possess oppositional levels of worry, elevating the importance of shared decision-making when patients face treatment equivalence. Trial Registration: ClinicalTrials.gov Identifier: NCT02609685.

Testosterone for low libido in postmenopausal women not taking estrogen.

BACKGROUND: The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown. METHODS: We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. RESULTS: At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization. CONCLUSIONS: In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

Testosterone reference ranges in normally cycling healthy premenopausal women.

INTRODUCTION: At present, there are no well-accepted reference ranges for serum testosterone concentrations in women. AIM: The aim of this study was to determine the reference ranges for serum testosterone and sex hormone-binding globulin (SHBG) in premenopausal women with normal menstrual cycles. METHODS: We measured serum total, free, and bioavailable testosterone and SHBG concentrations in 161 healthy, normally cycling women (18-49 years). Morning blood samples were collected during follicular, mid-cycle, and luteal phases of the menstrual cycle and analyzed using validated methods. Mean, median, and weighted average hormone levels across menstrual cycle phases as well as percentiles for a typical 30-year-old woman were determined. MAIN OUTCOME MEASURES: Age-related serum levels of total, free, and bioavailable testosterone and SHBG levels in normally cycling premenopausal women. RESULTS: Serum testosterone concentrations exhibited an age-related decline, whereas SHBG remained relatively stable across studied age ranges. Reference ranges for total, free, and bioavailable testosterone and SHBG were established using 5th and 95th percentiles. The estimated 5th and 95th percentiles for a 30-year-old woman were: testosterone, 15-46 ng/dL (520-1595 pmol/L); free testosterone, 1.2-6.4 pg/mL (4.16-22.2 pmol/L); calculated free testosterone, 1.3-5.6 pg/mL (4.5-19.4 pmol/L); bioavailable testosterone, 1.12-7.62 ng/dL (38.8-264.21 pmol/L); and SHBG 18-86 nmol/L. The variations of hormones and SHBG across menstrual cycle were consistent with previous literature. CONCLUSIONS: Reference ranges for free, total, and bioavailable testosterone and SHBG were established in premenopausal women using validated immunoassays and an adequate number of subjects consistent with recommendations by the National Committee for Clinical Laboratory Standards. The increase in testosterone in the mid-cycle period is relatively small compared with the overall variability, so these reference ranges can be applied irrespective of the day in the menstrual cycle the sample has been taken.

Update on subclinical hyperthyroidism.

Subclinical hyperthyroidism is defined by low or undetectable serum thyroid-stimulating hormone levels, with normal free thyroxine and total or free triiodothyronine levels. It can be caused by increased endogenous production of thyroid hormone (as in Graves disease or toxic nodular goiter), administration of thyroid hormone for treatment of malignant thyroid disease, or unintentional excessive thyroid hormone therapy. The rate of progression to overt hyperthyroidism is higher in persons who have suppressed thyroid-stimulating hormone levels compared with those who have low but detectable levels. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation in older adults, and with decreased bone mineral density in postmenopausal women; however, the effectiveness of treatment in preventing these conditions is unknown. There is lesser-quality evidence suggesting an association between subclinical hyperthyroidism and other cardiovascular effects, including increased heart rate and left ventricular mass, and increased bone turnover markers. Possible associations between subclinical hyperthyroidism and quality of life parameters, cognition, and increased mortality rates are controversial. Prospective randomized controlled trials are needed to address the effects of early treatment on potential morbidities to help determine whether screening should be recommended in the asymptomatic general population.

Incidental parathyroidectomy in thyroidectomy and central neck dissection.

BACKGROUND: Although higher thyroidectomy volume has been linked with lower complication rates, its association with incidental parathyroidectomy remains less studied. The volume relationship is even less clear for central neck dissection, where individual parathyroid glands are at greater risk. METHODS: Patients undergoing thyroidectomy with or without central neck dissection were evaluated for incidental parathyroidectomy, hypoparathyroidism, and hypocalcemia. Univariate and multivariable analyses were performed using binary logistic regression. RESULTS: Overall, 1,114 thyroidectomies and 396 concurrent central neck dissections were performed across 7 surgeons. Incidental parathyroidectomy occurred in 22.4% of surgeries (range, 16.9%-43.6%), affecting 7.1% of parathyroids at risk (range, 5.8%-14.5%). When stratified by surgeon, lower incidental parathyroidectomy rates were associated with higher thyroidectomy volumes (R2 = 0.77, P = .008) and higher central neck dissection volumes (R2 = 0.93, P < .001). On multivariable analysis, low-volume surgeon (odds ratio 2.94, 95% confidence interval 2.06-4.19, P < .001), extrathyroidal extension (odds ratio 3.13, 95% confidence interval 1.24-7.87, P = .016), prophylactic central neck dissection (odds ratio 2.68, 95% confidence interval 1.65-4.35, P <.001), and therapeutic central neck dissection (odds ratio 4.44, 95% confidence interval 1.98-9.96, P < .001) were the most significant factors associated with incidental parathyroidectomy. In addition, incidental parathyroidectomy was associated with a higher likelihood of temporary hypoparathyroidism (odds ratio 2.79, 95% confidence interval 1.45-5.38, P = .002) and permanent hypoparathyroidism (odds ratio 4.62, 95% confidence interval 1.41-5.96, P = .025), but not permanent hypocalcemia (odds ratio 1.27, 95% confidence interval 0.48-3.35, P = .63). Higher lymph node yield in central neck dissection was not associated with higher incidental parathyroidectomy rates (odds ratio 1.13, 95% confidence interval 0.85-8.81, P = .82). CONCLUSION: Higher surgical volume conferred a lower rate of incidental parathyroidectomy. Nonetheless, greater lymph node yield in central neck dissections did not result in greater parathyroid-related morbidity. Such findings support the value of leveraging surgical volume to both optimize oncologic resection and minimize complication rates.

Predictive Impact of Metastatic Lymph Node Burden on Distant Metastasis Across Papillary Thyroid Cancer Variants.

Background: While numerous factors determine prognosis in papillary thyroid carcinoma (PTC), distant metastasis (M1) represents one of the most dire. Escalating nodal burden and aggressive histology may contribute to higher metastatic risk, but this relationship is poorly defined and challenging to anticipate. We evaluate the predictive impact of these histological features on predicting distant metastases at initial presentation. Methods: Univariate and multivariable logistic regression models of conventional and aggressive thyroid cancer variants (well-differentiated papillary thyroid carcinoma [WDPTC], diffuse sclerosing variant [DSV], tall cell variant [TCV], poorly differentiated thyroid cancer [PDTC], and anaplastic thyroid carcinoma [ATC]) identified via U.S. cancer registry data were constructed to determine associations between M1 status and quantitative nodal burden. Associations between metastatic lymph node (LN) number and M1 disease were modeled using univariate and multivariable logistic regression with interaction terms, as well as a linear continuous probability model. Results: Overall, M1 prevalence at disease presentation was 3.6% (n = 1717). When stratified by subtype, M1 prevalence varied significantly by histology (WDPTC [1.0%], DSV [2.3%], TCV [4.1%], PDTC [17.4%], ATC [38.4%] [p < 0.001]). For WDPTC, M1 prevalence escalated with metastatic LN number (0 LN+ [0.5%], 1-5 LN+ [2.0%], 6-10 LN+ [3.4%], >10 LN+ [5.5%] [p < 0.001]) and LN ratio (p < 0.001). A statistically significant interaction was observed between histology and increasing nodal burden for M1 risk. On multivariable analysis, each successive metastatic LN conferred increased M1 risk for WDPTC (odds ratio [OR] 1.06 [1.05-1.08], p < 0.001) and TCVs (OR 1.04 [1.02-1.07], p < 0.001). In contrast, other aggressive variants had a higher baseline M1 risk, but this did not vary based on the number of positive LN (DSV, OR 1.02 [0.95-1.10], p = 0.52; PDTC, OR 1.00 [0.98-1.02], p = 0.66; ATC, 1.00 [0.98-1.02], p = 0.97). Conclusions: Progressive nodal burden independently escalates the risk of distant metastasis in WDPTC and TCVs of PTC. Conversely, aggressive variants such as PDTC and ATC have substantial M1 risk at baseline and appear to be minimally affected by metastatic nodal burden. Consideration of these factors after surgery may help tailor clinical decision-making for treatment and surveillance. Further studies are warranted to calibrate the ideal management approach for these higher risk patient groups.

The presentation of hypoactive sexual desire disorder in premenopausal women.

INTRODUCTION: Little is known about the clinical presentation of hypoactive sexual desire disorder (HSDD) in premenopausal women or their perceptions of sexual problems. AIM: Describe characteristics of premenopausal women with clinically diagnosed acquired, generalized HSDD, and investigate factors perceived to contribute to desire problems. METHODS: Cross-sectional analysis of baseline data from premenopausal women with clinically diagnosed and confirmed HSDD enrolled during the first year of the HSDD Registry for Women (N=400). MAIN OUTCOME MEASURES: Relationship, demographic, and clinical characteristics were assessed by clinician's medical history review and self-administered questionnaire. Sexual desire function was measured by the validated Female Sexual Function Index (FSFI). RESULTS: Over 85% of women cited multiple factors that contributed to ongoing decreased desire (mean 2.9± 2.3 factors, range 0-12). Most commonly cited contributing factors were "stress or fatigue" (60.0%), "dissatisfaction with my physical appearance" (40.8%), and other sexual difficulties (e.g., inability to reach orgasm) (33.5%). Exploratory analyses of the FSFI score confirmed that self-image (P=0.002) and other sexual problems (P<0.001) were significantly associated with decreased desire. Almost all (96%) participants were currently in a partner relationship. Antidepressant medication was currently used by 18.0% of women, hormonal contraceptives by 28.5%, and hormonal medications (for noncontraceptive reasons) by 7.3%. Physical functioning was consistent with general population norms (SF-36 mean±standard deviation, 53.3±7.6 vs. norm of 50±10), while overall mental functioning was slightly lower (SF-36, 44.7±10.6). CONCLUSIONS: Within this sample of premenopausal women with clinically diagnosed HSDD, decreased sexual desire was associated with multiple factors, including poor self-image and stress or fatigue. Clinicians presented with premenopausal women expressing sexual desire problems should assess patients' perceptions of their condition to develop a comprehensive, patient-oriented management plan. Therapy may need to address issues with low self-esteem and mood and offer practical coping mechanisms for stress and fatigue.

Differences in total human chorionic gonadotropin immunoassay analytical specificity and ability to measure human chorionic gonadotropin in gestational trophoblastic disease and germ cell tumors.

OBJECTIVE: To determine the ability of several radioimmunoassays and commercial two-site immunoassays to detect the first World Health Organization International Reference Reagents (IRRs) for 6 defined human chorionic gonadotropin (hCG) variants and to compare their performance in measuring hCG in sera from patients with gestational trophoblastic disease (GTD) and germ cell tumors (GCTs) of the testis or ovary. STUDY DESIGN: The reactivity of the different assays with the 6 IRRs together with the current fourth International Standard (IS, 75/589) was tested using 5 commercial two-site assays as well as 2 competitive polyclonal radioimmunoassays (RIAs) and a competitive monoclonal immunoassay. Individual samples from 41 patients (19 GCT and 22 GTD) with high circulating levels of hCG (range, 718-6,055,000 IU/L) were diluted and measured using the various immunoassays. RESULTS: The results of 4 GCT patient samples varied markedly among the assays, including 1 sample that was grossly underestimated by 3 of the commercial assays. CONCLUSION: Comparison of each assay's reactivity to the variant isoforms revealed that recognition of the isoforms was highly variable, particularly for hCGbeta and hCGbeta core fragment (hCGbetacf).

Incidence and Mortality Risk Spectrum Across Aggressive Variants of Papillary Thyroid Carcinoma.

Importance: While well-differentiated papillary thyroid carcinoma (WDPTC) outcomes have been well characterized, the prognostic implications of more aggressive variants are far less defined. The rarity of these subtypes has led to their consolidation as intermediate risk for what are in fact likely heterogeneous diseases. Objective: To analyze incidence, clinicopathologic characteristics, and outcomes for aggressive variants of papillary thyroid carcinoma (PTC). Design, Setting, and Participants: This cohort study used data from 2000 to 2016 from hospital-based and population-based US cancer registries to analyze aggressive PTC variants, including diffuse sclerosing (DSV), tall-cell (TCV), insular, and poorly differentiated (PDTC) subtypes. These variants were compared against WDPTC and anaplastic cases. Data analysis was conducted from January 2019 to October 2019. Main Outcomes and Measures: Age-adjusted incidence was calculated via annual percentage change (APC) using the weighted least-squares method. Overall survival and disease-specific survival were analyzed via Cox regression. Propensity-score matching was used to adjust survival analyses for clinical and demographic covariates. Results: Collectively, 5447 aggressive PTC variants were identified (including 415 DSV, 3339 TCV, 362 insular, and 1331 PDTC cases), as well as 35 812 WDPTC and 2249 anaplastic cases. Over the study period, a substantial increase in aggressive variant incidence was observed (APC, 9.1 [95% CI, 7.33-10.89]; P < .001), surpassing the relative increases observed in WDPTC (APC, 5.1 [95% CI, 3.98-6.12]; P < .001) and anaplastic cases (APC, 1.9 [95% CI, 0.75-3.05]; P = .003; parallelism P < .007). Survival varied markedly based on histologic subtype, with a wide spectrum of mortality risk noted; 10-year overall survival was 85.4% (95% CI, 84.6%-86.3%) in WDPTC, 79.2% (95% CI, 73.6%-85.3%) in DSV, 71.9% (95% CI, 68.4%-75.6%) in TCV, 45.1% (95% CI, 40.2%-50.6%) in PDTC, 27.9% (95% CI, 20.0%-38.9%) in the insular variant, and 8.9% (95% CI, 7.5%-10.6%) in anaplastic cases (P < .001). These differences largely persisted even after adjusting for inherent differences in baseline characteristics by multivariable Cox regression and propensity-score matching. Conclusions and Relevance: An upsurge in aggressive PTC incidence was observed at a rate beyond that seen in WDPTC or anaplastic thyroid carcinoma. Moreover, long-term survival outcomes for aggressive PTC subgroups exhibit heterogeneous clinical behavior and a wide range of mortality risk, suggesting that treatment should be tailored to specific histologic subtypes. Given increasing prevalence and disparate outcomes, further investigation to identify optimal therapeutic strategies is needed in these diverse, understudied populations.